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. Author manuscript; available in PMC: 2021 Mar 1.
Published in final edited form as: Cancer Treat Rev. 2020 Jan 17;84:101965. doi: 10.1016/j.ctrv.2020.101965

HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: a systematic review and meta-analysis

Francesco Schettini a,b,c,1, Tomas Pascual b,c,d,1, Benedetta Conte e, Nuria Chic c,d, Fara Brasó-Maristany b,d, Patricia Galván b, Olga Martínez b,d, Barbara Adamo b,c,d, Maria Vidal b,c,d, Montserrat Muñoz b,c,d, Aranzazu Fernández-Martinez f, Carla Rognoni g, Gaia Griguolo h,i, Valentina Guarneri h,i, Pier Franco Conte h,i, Mariavittoria Locci j, Jan C Brase k, Blanca Gonzalez-Farre l, Patricia Villagrasa c, Sabino De Placido a, Rachel Schiff m,n,o,p, Jamunarani Veeraraghavan m,n, Mothaffar F Rimawi m,n,o, C Kent Osborne m,n,o,p, Sonia Pernas c,q,r, Charles M Perou f, Lisa A Carey s, Aleix Prat b,c,d
PMCID: PMC7230134  NIHMSID: NIHMS1583643  PMID: 32000054

Abstract

Background:

HER2-positive (HER2+) breast cancer (BC) comprises all the four PAM50 molecular subtypes. Among these, the HER2-E appear to be associated with higher pathological complete response (pCR) rates following anti-HER2-based regimens. Here, we present a meta-analysis to validate the association of the HER2-E subtype with pCR following anti-HER2-based neoadjuvant treatments with or without chemotherapy (CT).

Methods:

A systematic literature search was performed in February 2019. The primary objective was to compare the association between HER2-E subtype (versus others) and pCR. Selected secondary objectives were to compare the association between 1) HER2-E subtype and pCR in CT-free studies, 2) HER2-E subtype within hormone receptor (HR)-negative and HR+ disease and 3) HR-negative disease (versus HR+) and pCR in all patients and within HER2-E subtype. A random-effect model was applied. The Higgins’ I2 was used to quantify heterogeneity.

Results:

Sixteen studies were included, 5 of which tested CT-free regimens. HER2-E subtype was significantly associated with pCR in all patients (odds ratio [OR]=3.50, p<0.001, I2=33%), in HR+ (OR=3.61, p<0.001, I2=1%) and HR-negative tumors (OR=2.28, p=0.01, I2=47%). In CT-free studies, HER2-E subtype was associated with pCR in all patients (OR=5.52, p<0.001, I2=0%) and in HR+ disease (OR=4.08, p=0.001, I2=0%). HR-negative status was significantly associated with pCR compared to HR+ status in all patients (OR=2.41, p<0.001, I2=30%) and within the HER2-E subtype (OR=1.76, p<0.001, I2=0%).

Conclusions:

The HER2-E biomarker identifies patients with a higher likelihood of achieving a pCR following neoadjuvant anti-HER2-based therapy beyond HR status and CT use. Future trial designs to escalate or de-escalate systemic therapy in HER2+ disease should consider this genomic biomarker.

Keywords: PAM50, breast cancer, HER2-positive, HER2-enriched, biomarker, pathologic complete response

INTRODUCTION

Breast cancer (BC) with overexpression and/or amplification of the Human Epidermal Growth Factor Receptor 2 (HER2-positive) represents 11-30% of all breast tumors1. HER2 positivity is defined today by immunohistochemistry (IHC) as complete and strong membrane staining (i.e. score of 3+) in ≥10% of cancer cells, and/or by in situ immunofluorescence (ISH) techniques as amplified using a HER2/CEP17 ratio cutoff of ≥ 2.0 and an average HER2 gene copy number ≥ 4.0 signals per cell2. This consensus definition is based on the methods and cutoffs used over the years in pivotal trials that led to the approval of trastuzumab3, pertuzumab4, neratinib5, lapatinib6 and T-DM17 in HER2+ breast cancer.

The current HER2 definition do not sufficiently consider HER2+ disease’s clinical and biological heterogeneity. On one hand, high variability in patient’s response and survival outcomes following anti-HER2-based therapy is common8,9. On the other hand, high biological variability exists within HER2+ disease1012. For example, all the BC intrinsic subtypes [i.e. Luminal A, Luminal B, HER2-enriched (HER2-E) and Basal-like] can be identified through gene expression profiling9,10,13. Among them, the HER2-E subtype is the most frequent (31-76%), shows the highest levels of ERBB2 mRNA and protein and appears to be the subtype with the highest activation of the EGFR-HER2 signaling pathway11,1431. Importantly, these biological entities within HER2+ disease are not fully recapitulated by hormone receptor (HR) status since 40% of HER2+/HR+ tumors are HER2-E and 15% of HER2+/HR-negative tumors are Basal-like10,11,32.

To date, no biomarker has demonstrated clinical utility in HER2+ early disease beyond HER2 and HR status33. However, accumulating evidence supports the clinical validity of two biomarkers: intrinsic subtyping and stromal tumor infiltrating-lymphocytes (TILs). In particular, either the HER2-E subtype or high TILs appears to be associated with high response to anti-HER2-based treatments in the neoadjuvant setting1431,34,35. From a prognostic point of view, however, HER2-E subtype is associated with a worse prognosis10,36 whereas TILs are associated with a better survival outcome34,37,38. Unfortunately, the majority of these data were derived from retrospective analyses from individual clinical trials using baseline tumor samples. In addition, most analyses were exploratory and unplanned, and limited by relatively small sample sizes.

To increase the level of evidence of the association of the HER2-E subtype with the response to anti-HER2 based neoadjuvant regimens, we decided to review the literature and perform a meta-analysis.

MATERIALS AND METHODS

Search strategy and selection criteria

A systematic literature search was performed on 12/February/2019 to identify published observational, phase II and phase III (randomized and non-randomized) neoadjuvant clinical studies involving anti-HER2-based treatments in HER2+ BC, where the association between pathological complete response (pCR) and BC molecular intrinsic subtypes was evaluated. The literature search had no time nor language restriction, however, only clinical studies involving anti-HER2-based neoadjuvant regimens were included, with or without chemotherapy. Additional studies particularly relevant to the topic, for which molecular data had not been published but were available at the Translational Genomic and Targeted Therapeutics in Solid Tumors laboratory of the IDIBAPS (Barcelona, Spain), were also included in the analysis. All pre-clinical studies, phase I trials, non-neoadjuvant trials and neoadjuvant trials without anti-HER2 agents were excluded. The recommendations of the Cochrane Collaboration44 were followed to identify all relevant studies. For our query, we used a combination of disease characteristics, study design, treatment setting and strategies or drugs. The full query is reported in the Suppl. Materials. Both full articles and studies published in the abstract form were included in the analysis, if odds ratios (OR) data were directly available or computable. The search was conducted on the electronic databases Pubmed and Web of Science®, as well as on San Antonio Breast Cancer Symposiums (SABCS)’s, American Society of Clinical Oncology (ASCO)’s and European Society of Medical Oncology (ESMO)’s annual meetings online archives. Four reviewers (FS, TP, NC and CR) independently evaluated whether each selected randomized clinical trials (RCT) respected the predetermined criteria, and another reviewer (AP) was consulted in case of controversy.

Data extraction and objectives

Details on study design, patient/tumor characteristics, interventions and outcome were extracted from each paper. Only the most recent and complete reports were included when duplicate publications were identified. Crude odds ratio (OR) for pCR with their 95% confidence intervals (CI) were extracted or calculated, when necessary, from each published paper or internal datasets. The definition of pCR varied across studies. In 12/16 (75%) studies (2,176/2,703 patients with known PAM50 subtype), pCR was defined as the absence of invasive neoplastic cells at microscopic examination of the primary tumor at surgery in breast and axilla (pCR in-breast and axilla), with remaining in-situ lesions allowed. In 4/16 (25%) studies (527/2,703 patients with known molecular subtype), pCR was defined as the absence of tumor cells only in breast, without considering tumor response in axillary lymph nodes (pCR in-breast).

The primary objective was to compare the association between HER2-E subtype (versus others) and pCR in all patients. Secondary objectives were to:

  1. compare the association between HER2-E subtype (versus others) and pCR in CT-free studies;

  2. compare the association between HR-negative disease (versus HR+) and pCR in all patients;

  3. compare the association between HR-negative disease (versus HR+) and pCR within HER2-E subtype;

  4. compare the association between HER2-E subtype (versus others) and pCR within HR+ and HR-negative disease;

  5. compare the association between each intrinsic subtype (versus the others) and pCR.

Statistical analyses

Since a certain degree of heterogeneity was expected, analyses were performed under the Random-Effect Model of DerSimonian and Laird45. Heterogeneity was assessed with Higgin’s I2 index46. Pre-planned exploratory subgroup analyses for the primary endpoint were conducted, even if heterogeneity was not relevant. Subgroup analyses of interest were: 1) phase II vs phase III trials, 2) randomized vs. non-randomized trials 3) CT-containing vs. CT-free studies 4) pCR in-breast vs pCR in-breast and axilla. For the primary endpoint, to assess whether the pooled OR estimates were stable or strongly dependent on one or few studies, sensitivity analyses were conducted by interactively recalculating the pooled OR estimates after exclusion of each single study. Publication bias was explored through funnel plot visual inspection and the Egger’s linear regression test for funnel plot asymmetry47,48. All reported p values were two-sided. All statistical analyses and the generation of forest plots were conducted using R and RevMan49,50. The Cochrane risk of bias assessment tool was employed to assess the quality of the data obtained and the risk of bias in each study. Significance was set at p<0.05, except for Egger’s test, for which significance was set as p<0.1, as usual. The project was registered in the PROSPERO online database51, with registration number: CRD42019140902.

Assessment of risk of bias

The risk of bias for each trial was assessed by using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions44. Each domain related to a risk of bias was assessed in each included trial, since there is evidence that these issues are associated with biased estimates of treatment effect. The domains were the following: 1) random sequence generation; 2) allocation concealment; 3) blinding of participants and personnel; 4) blinding of outcome assessment; 5) incomplete outcome data; 6) selective reporting; 7) other bias. Review authors’ judgments were categorized as “low risk”, “high risk” or “unclear risk” of bias. Internal validity of eligible studies was assessed according to the Cochrane Collaboration’s ‘Risk of Bias’ tool in Review Manager50.

RESULTS

Summary of studies and patient characteristics

A total of 16 studies were included (Tables 1 and 2; Supplementary Tables 1 and 2)1431. From Pubmed and Web of Science® online databases, 2,207 studies were extracted and 10 were included1418,2022,24,25,28. From ASCO, ESMO and SABCS online abstracts books, 4 studies were included19,26,27,30,31. Finally, data from 2 studies (ICO-CLINIC, LPT109096) were available at the Translational Genomic and Targeted Therapeutics in Solid Tumors laboratory at IDIBAPS (Barcelona, Spain)14,26,31. Some data were also retrieved from later-published full articles11,52. The selection process is resumed in the PRISMA diagram (Fig. 1). Overall 5 (31.25%) phase III RCT, 5 (31.25%) phase II RCT, 5 (31.25%) non-randomized phase II trials and 1 (6.25%) retrospective observational study were included. All the articles/abstracts containing molecular results have been published between 2014 and 2019.

Table 1.

Characteristics of the included randomized phase II and III trials

RANDOMIZED TRIALS
Study name NOAH* NSABP-B41 NeoALTTO CALGB40601 KRISTINE Cher-LOB NeoSphere TRYPHAENA LPT109096 TBCRC023
Phase III III III III III II II II II II
Regimen Dox+P→P→CMF→T (HER2 positive cohort) AC→P+T AC→P+L AC→P+T+L L+T→P L→P T→P L+T+P L+P T+P TCH+Pe T-DM1+Pe L+T→P→FEC L→P→FEC T→P→FEC T+D Pe+T+D Pe+T Pe+D FEC+T+Pe→T+Pe+D FEC→T+Pe+D TCH+Pe T+FECT+P L+FECL+P T+L+FECT+L+P L+T +/− Let +/− GnRHa 12 weeks L+T +/− Let +/− GnRHa 24 weeks
Treatment category anti-HER2+CT anti-HER2+CT anti-HER2+CT anti-HER2+CT anti-HER2+CT anti-HER2+CT anti-HER2+CT anti-HER2+CT anti-HER2+CT anti-HER2 w/o CT
N. of evaluable patients/Total of the arm 63/117 271/529 254/455 262/305 354/444 84/121 337/417 173/225 61/100# 85/97
TNM Stage III II and III II and III II and III II and III II and IIIA II and III II and III II and III II and III
HR status Pos and neg Pos and neg Pos and neg Pos and neg Pos and neg Pos and neg Pos and neg Pos and neg Pos and neg Pos and neg
HER2E(%) 34 (54.0) 197 (72.7) 110 (43.3) 82 (31.3) 194 (54.8) 22 (26.2) 135 (40.1) 82 (47.4) 41 (67.2) 51 (60.0)
non-HER2E (%) 29 (46.0) 74 (27.3) 144 (56.7) 180 (68.7) 160 (45.2) 62 (73.8) 202 (59.9) 91 (52.6) 20 (32.8) 34 (40.0)
pCR in HER2E (%) 18 (62.1) 120 (60.9) 57 (51.8) 57 (69.5) 131 (67.5) 11 (50.0) 53 (39.3) 57 (69.5) 30 (73.1) 14 (27.5)
pCR in non-HER2E (%) 10 (34.5) 19 (25.7) 31 (21.5) 64 (35.6) 47 (29.4) 16 (25.8) 52 (25.7) 46 (50.5) 15 (75.0) 3 (8.8)
pCR definition ypT0/is ypN0 ypT0/is ypN0 ypT0/is ypN0 ypT0/is ypT0/is ypN0 ypT0/is ypN0 ypT0/is ypN0 ypT0/is ypN0 ypT0/is ypN0 ypT0/is
Gene expression platform Microarray-based nCounter RNA seq. RNA seq. nCounter Microarray-based nCounter nCounter nCounter nCounter
Data source Published material Published material Published material Published material Published material Published material Published material Published material IDIBAPS lab Published material
Year of publication 2014 2013/2019 2012/2016 2015 2017 2015/2016 2012/2018 2013 2011 2019/2019
First author Prat A Robidoux A/Swain SM Baselga J/Fumagalli D Carey L Prat A Guameri V/Dieci MV Gianni L/Bianchini G Schneeweiss A Holmes FA Rimawi MF/Prat A
Publication form Full article Full article Full article Full article Abstract Full article Full article/Abstract/Poster Full article Full article/intemal data Full article/Full article
Publication site Clin Can Res Lancet Oncol/Breast Can Res Treat Lancet/JAMA Oncol J Clin Oncol SABCS The Oncologist/Ann Oncol Lancet Oncol/ESMO congress Ann Oncol BMC Research Notes/Internal data Clin Cancer Res/JNCI

HER2E=HER2 enriched; non-HER2E=Basal-Like, Luminal A, Luminal B, Normal-like; Pos=positive; Neg=negative; HR=hormone receptors; CT=chemotherapy; N/A=not assessed; pCR=pathologic complete response; AC=doxorubicin+cyclophosphamide; Dox=doxorubicin; CMF=cyclophosphamide+methotrexate+5-fluorouracil; FEC=5-fluorouracil+epirubicin+cyclophosphamide; TCH=docetaxel+carboplatin+trastuzumab; P=paclitaxel; D=docetaxel; LD=liposomal doxorubicin; T=trastuzumab; Pe=pertuzumab; L=lapatinib; Let=letrozole; GnRHa=GnRH analogue → = followed by;

*

:HER2 positive cohort non-treated with trastuzumab and HER2 negative cohort not considered;

#

: pts with non-available information on pCR excluded;

SABCS=San Antonio Breast Cancer Symposium; ASCO=American Society of Clinical Oncology; ESMO=European Society for Medical Oncology

Table 2.

Characteristics of the included non-randomized studies

NON-RANDOMIZED STUDIES
Study name ICO-CLINIC BERENICE Opti-HER HEART PerELISA TBCRC006 PAMELA
Study type Retrospective Observational Non-randomized Phase II Single Ann Phase II Non-Randomized Phase II Single Ann Phase II Single Ann Phase II
Regimen Tax+/−Anthra+T ddAC→P+T+Pe FEC→D+T+Pe Pe+T+LD+P Let+T+Pe P+T+Pe L+T +/− Let+/− GnRH L+T +/− Let or Tam
Treatment category anti-HER2+CT anti-HER2+CT anti-HER2+CT anti-HER2 w/o CT anti-HER2+CT anti-HER2 w/o CT anti-HER2 w/o CT
N. of evaluable patients/Total of the arm 172/173 294/400 58/83 40/44 15/17 29/65 151/151
TNM Stage I-III II and III II and III II and III II and III I-III
HR status Pos and neg Pos and neg Pos and neg Pos Pos and neg Pos and neg
HER2E (%) 102 (59.3) 175 (59.5) 30 (51.7) 11 (27.5) 12 (75.0) 22 (75.9) 101 (66.9)
non-HER2E (%) 70 (40.7) 119 (40.5) 28 (48.3) 29 (72.5) 3 (25.0) 7 (24.1) 50 (33.1)
pCR in HER2E (%) 63 (61.8) 130 (74.2) 25 (83.3) 5 (45.5) 10 (83.3) 6 (20.7) 41 (40.6)
pCR in non-HER2E (%) 19 (27.1) 52 (43.7) 13 (46.4) 4 (13.8) 2 (66.7) 1 (14.3) 5 (10.0)
pCR definition ypT0/is ypN0 ypT0/is ypN0 ypT0/is ypN0 ypT0/is ypN0 ypT0/is ypT0/is
Gene expression platform nCounter nCounter nCounter nCounter nCounter nCounter
Data source Published material/Internal data Published material Published material Published material Published material Published material
Year of publication 2017/2019 2017 2019 2019 2013/2019 2017
First author Pernas S Swain SM Gavilà J Guarneri V Rimawi MF/Prat A Llombart-Cussac A
Publication form Abstract/Full article Full article Full article Full article Full article Full article
Journal/Meeting SABCS /Front Oncol Ann Oncol BMC Medicine Ann Oncol J Clin Oncol/JNCI Lancet Oncol

HER2E=HER2 enriched; non-HER2E=Basal-Like, Luminal A, Luminal B, Normal-like; Pos=positive; Neg=negative; HR=hormone receptors; CT=chemotherapy; N/A=not assessed; pCR=pathologic complete response; AC=doxorubicin+cyclophosphamide; Dox=doxorubicin; CMF=cyclophosphamide+methotrexate+5-fluorouracil; FEC=5-fluorouracil+epirubicin+cyclophosphamide; TCH=docetaxel+carboplatin+trastuzmnab; Tax=taxanes; Anthra=anthracyclines; P=paclitaxel; D=docetaxel; LD=liposomal doxombicin; T=trastuzumab; Pe=pertuzumab; L=lapatinib; Let=letrozole; Tam=tamoxifen; GnRHa=GnRH analogue; → = followed by; dd=dose dense.

Fig. 1.

Fig. 1.

PRISMA diagram.

From a total of 3,733 patients, PAM50 intrinsic subtype was available for 2,703 (72.4%) patients, while HRs status was known for 3,373 (90.3%) patients. Except for one trial (i.e. PerELISA) which enrolled HR+ tumors-only28, the others included both HR+ and HR-negative tumors. All studies included evaluated anti-HER2-based neoadjuvant regimens with or without CT14,23,28,29,53, and included tumor stages II or III, except for the PAMELA trial and the retrospective observational study from the Catalan Institute of Oncology and the Hospital Clinic of Barcelona (ICO-CLINIC), which allowed stage I disease14,26. Various methods for assessing the PAM50 BC intrinsic subtypes were used across all trials (Tables 12), but all were based upon gene expression data1431.

Among the studies included, only the PAMELA single arm phase II trial was specifically designed to prospectively assess PAM50 intrinsic subtypes and test whether patients with the HER2-E subtype benefited more than the other subtypes from a neoadjuvant anti-HER2-based CT-free regimen14. The other studies evaluated PAM50 as an exploratory retrospective analysis; therefore, tumor samples were not always available for all patients included. However, samples were always available for at least half of the population enrolled within each study (Tables 12). pCR rates in HER2-E subtype were higher than nonHER2-E subtypes in each study, except in the LPT109096 trial. Individual trials’ results are reported in Tables 1 and 2.

pCR and HER2-E subtype

The HER2-E subtype was significantly associated with pCR compared to others (OR=3.50, 95% CI 2.79 – 4.39, p<0.001, I2=33%, Fig. 2). The funnel plot suggested the absence of publication bias (Suppl. Fig. 1), confirmed by a non-significant Egger’s test (p=0.48). The influential analysis showed consistent results when omitting a single trial with an I2 range varying from 3.4% (omitting the NeoSphere trial)20 to 37.7% (omitting the TBCRC023 trial)31. Full results of the influential analysis are reported in Table 3. Considering the absence of significant heterogeneity, an exploratory, non-preplanned analysis done with the fixed-effect model54 was performed with a similar result (OR=3.51, 95% CI: 2.96 – 4.16, p<0.001, I2=33%).

Fig. 2.

Fig. 2.

Forest Plots comparing the association with pCR between the HER2-E and the other intrinsic subtypes in the overall population.

Table 3.

Influential analyses concerning the primary end-point

Study Omitted OR 95% CI p I2

BERENICE 3.47 2.70 – 4.47 <0.0001 37.6%
CALGB40601 3.44 2.68 – 4.40 <0.0001 36.7%
Cher-LOB 3.52 2.78 – 4.48 <0.0001 37.4%
ICO-CLINIC 3.43 2.69 – 4.38 <0.0001 36.6%
KRISTINE 3.34 2.63 – 4.23 <0.0001 28.9%
LPT109096 3.62 2.95 – 4.45 <0.0001 21.3%
NeoALTTO 3.45 2.69 – 4.43 <0.0001 37.3%
NEOSPHERE 3.85 3.18 – 4.66 <0.0001 3.4%
NOAH 3.57 2.82 – 4.50 <0.0001 35.2%
NSABP-B41 3.41 2.67 – 4.35 <0.0001 35.6%
Opti-HER-HEART 3.44 2.72 – 4.35 <0.0001 35.9%
PAMELA 3.41 2.71 – 4.30 <0.0001 34.1%
Per-ELISA 3.41 2.72 – 4.28 <0.0001 32.3%
TBCRC006 3.51 2.78 – 4.43 <0.0001 37.4%
TBCRC023 3.48 2.75 – 4.42 <0.0001 37.7%
TRYPHAENA 3.64 2.88 – 4.59 <0.0001 31.2%

OR=odds ratio; CI=confidence intervals

There were no statistically significant differences in terms of association with pCR for all the subgroups considered for the preplanned sensitivity analyses, namely randomized vs. non-randomized studies (p=0.46), phase II vs. phase III studies (p=0.13), CT-containing vs. CT-free studies (p=0.30), pCR in-breast vs pCR in-breast+axilla (p=0.32). Compared to other intrinsic subtypes, the HER2-E subtype was significantly associated with pCR compared to Basal-like (OR=2.50, 95% CI 1.78 – 3.52, p<0.001, I2=0%, Suppl. Fig. 2A), Luminal A (OR=4.81, 95% CI 3.16 – 7.33, p<0.001, I2=55%, Suppl. Fig. 2B), Luminal B (OR=3.82, 95% CI 2.97 – 4.91, p<0.001, I2=0%, Suppl. Fig. 2C) and Luminal A/B (OR=4.36, 95% CI 3.17 – 6.00, p<0.001, I2=52%, Suppl. fig. 2D) subtypes. Other comparisons among intrinsic subtypes can be found in the Suppl. Materials.

pCR, HR status and HER2-E subtype

Fifteen of the 16 trials were used to assess the association between HR status and pCR. HR-negative disease was significantly associated with pCR compared to HR+ disease (OR=2.41, 95% CI 2.00 – 2.92, p<0.001, I2=30%, Fig. 3A). The inspection of the funnel plot (Suppl. Fig. 3), as well as the result of the Egger’s test (p=0.68), did not reveal a significant publication bias. The HER2-E subtype was significantly associated with pCR within both HR-negative disease (OR=2.28, 95% CI 1.21 – 4.29, p=0.01, I2=47%, Fig. 3B) and HR+ disease (OR=3.61, 95% CI 2.61 – 5.00, p<0.001, I2=1%, Fig. 3C). Similar to what was observed for the general population, HR-negative disease was significantly associated with pCR compared to HR+ disease within the HER2-E subtype (OR=1.76, 95% CI 1.30 – 2.38, p<0.001, I2=0%, Fig. 3D).

Fig. 3.

Fig. 3

A-D. Forest Plots comparing the association with pCR between HR-positive and HR-negative tumors (A) in the overall population; the association with pCR between the HER2-E and the other intrinsic subtypes within the HR-negative (B) and HR-positive (C) disease, and the association of pCR between HR-positive and HR-negative tumors within the HER2-E subtype (D).

pCR, HR status and HER2-E subtype in the absence of CT

A total of 5 studies evaluated dual HER2 blockade in the absence of CT14,20,28,29,31, although for one of these (i.e. NeoSphere), data for the CT-free arm were not available separately from the other CT-containing arms’ data 20. In CT-free regimens, HER2-E subtype was significantly associated with pCR compared to the other subtypes (OR=5.52, 95% CI 2.89 – 10.54, p<0.001, I2=0%, Fig. 4A), while there was no apparent difference between HR-negative vs. HR+ disease (OR=1.49, 95% CI 0 44 – 5.03, p=0.52, I2=76%, Fig. 4B). When considering HR status, the HER2-E subtype was found to be significantly associated with pCR within HR+ disease (OR=4.08, 95% CI: 1.76 – 9.46, p=0.001, I2=0%, Suppl. Fig. 4A), but not within HR-negative disease (OR=2.18, 95% CI: 0.66 – 7.26, p=0.20, I2=0%, Suppl. Fig. 4B). Conversely, in patients with HER2-E subtype, HR status was not significantly associated with pCR (OR=1.30, 95% CI 0.67 – 2.52, p=0.44, I2=0%, Suppl. Fig. 5).

Fig. 4.

Fig. 4.

Forest Plots comparing the association with pCR between the HER2-E and the other subtypes (A), and between HR-negative and HR-positive tumors (B) in CT-free trials.

Risk of bias analysis

With respect to the risk of bias, as defined by the Cochrane’s manual for systematic reviews44, the risk of selection bias for random sequence generation and allocation concealments was present in the 6/16 (37.5%) of the studies in both cases, with an unclear risk in 1/16 (6.25%) studies included, concerning the random sequence generation selection bias (Fig. 5 and Suppl. Fig. 6). The performance bias due to blinding of participants and personnel was present in 12/16 (75%) of cases, with an unclear risk in 3/16 (18.75%) of the studies included. No detection bias related to the blinding of outcome assessment, attrition bias due to incomplete outcome data and selective reporting bias were observed. Concerning the last two, an unclear risk was present in 1/16 (6.25%) cases. Finally, we accounted for a 6.25% high risk of other bias related to the ICO-CLINIC study, due to its retrospective and non-trial design.

Fig. 5.

Fig. 5.

Risk of bias analysis.

DISCUSSION

The development of effective drugs against HER2+ BC has been particularly successful in the last few years37. Since the introduction of trastuzumab3, other effective and tolerable anti-HER2 drugs (i.e. lapatinib, pertuzumab, neratinib and T-DM1) have been introduced in the metastatic and/or early disease settings, contributing to important improvements in survival outcomes8,55. However, HER2+ disease is clinically and biologically heterogeneous and not all patients benefit to the same extend from current treatments. Thus, better identification of patients using biomarkers should allow the design of prospective trials aiming to improve precision medicine in HER2+ BC.

Among the different biomarkers evaluated in HER2+ disease over the last decade10,14,21,31,34,35,37,39,40,56, the HER2-E subtype has been proposed to identify patients whose HER2+ tumors are HER2 “addicted” (meaning driven primarily by signaling via the HER2 pathway). Retrospective analysis of the HER2-E subtype, mostly exploratory and unplanned, using baseline tumor samples from individual clinical trials have linked this phenotype with high rates of pathological complete response following neoadjuvant anti-HER2-based therapies1431. However, to date, no combined analysis or meta-analysis has been performed and analyses within all of those studies were limited by relatively small sample sizes. Here, we performed a trial-level meta-analysis of 16 neoadjuvant studies and 2,703 patients to evaluate the association of the HER2-E subtype with pCR. In particular, we confirmed that the HER2-E subtype is a consistent biomarker to identify patients with a higher likelihood of achieving a pCR following anti-HER2-based therapy with or without cytotoxic therapy. Importantly, the association of the HER2-E subtype with pCR appeared to be independent of HR status, which is the only biomarker with clinical utility in HER2+ disease. Additionally, our results confirm the ability of HR status to predict pCR by itself and within the HER2-E subtype, although we could not demonstrate this in the CT-free setting, which had substantially fewer contributing trials.

We adopted pCR as our clinical endpoint for this meta-analysis. This is because numerous studies have demonstrated a favorable prognostic role in early stage HER2+ BC5660 so its use as primary endpoint in neoadjuvant trials has been increasing over the years and has also been endorsed for regulatory purposes by regulatory agencies such as US Food and Drug Administration (FDA), for accelerated approval of neoadjuvant treatments in high risk early-stage BC61. Furthermore, the FDA recently approved the use of adjuvant T-DM1 (in HER2+ BC) or capecitabine (in HER2-negative BC) in case of no achievement of pCR following standard neoadjuvant systemic therapy and surgery, making of pCR a fundamental tool in therapeutic decision-making in non-metastatic BC for escalating treatment strategies. At the same time, there is also an increasing use of pCR as a tool to identify potentially effective and safe de-escalating therapeutic approaches in HER2+ BC14,28,29,62. In fact, identification of effective de-escalating treatment strategies to spare toxicity and financial costs to patients is a main focus of the research community nowadays63,64. In adjuvant setting, several prospective trials of early stage HER2+ BC have attempted to demonstrate that de-escalating strategies based on a shorter duration of adjuvant trastuzumab provided similar benefits as the conventional 1 year; however, the results using non-inferiority trial designs were mixed65. On the contrary, a single-arm trial from a single institution (i.e. the APT trial) evaluating 12 doses of adjuvant weekly paclitaxel and 1-year of trastuzumab in largely HR+ stage I disease significantly impacted on daily clinical practice after showing extraordinary DFS and OS rates at 7-years66. In this scenario, at least 3 critical questions remain to be answered regarding de-escalation of systemic therapy in early HER2+ disease: 1) who can be treated with less or even no adjuvant trastuzumab after surgery? 2) who does not need (neo)adjuvant pertuzumab in stage II and III disease? 3) can we decrease the amount of chemotherapy? In fact, immunohistochemically HER2+/non-HER2-E tumors might be poorly dependent, if not totally independent, from the HER2-signaling pathway and not gain any benefit from adjuvant trastuzumab following previous neoadjuvant therapy and surgery. At the same time some HER2+ tumors might be “HER2 addicted” enough not to need chemotherapy at all or to require a shortened adjuvant trastuzumab duration and/or no adjuvant dual blockade therapy. To address these questions, well-designed clinical trials integrating clinical variables (such as tumor dimension and axillary nodes involvement), response data and biomarkers such as the HER2-E subtype, TILs, intra-tumor heterogeneity67 and PIK3CA status are needed.

This meta-analysis has several limitations. First, some secondary end-points were affected by discrete levels of heterogeneity (I2>75% and p heterogeneity<0.05, results in Fig. 4B and Suppl. Materials). This was mostly attributable to the paucity of molecular data from some trials and differences in the effects observed, preventing them from being fully reliable, regardless of the analytical model applied. However, this consideration doesn’t apply to the main result of the study. Second, although several studies correlated pCR with long-term survival outcomes (EFS/DFS and OS) in the context of HER2+ BC5660, others failed to demonstrate its role as an efficient surrogate endpoint for survival68,69. Additionally, there is a specific lack of survival data related to intrinsic subtypes within the clinical trials included in this study. Therefore, no claims regarding the association of HER2-E with patient’s survival outcome can be made based on this meta-analysis. Moreover, 4/16 trials reported data regarding in-breast pCR, which has not been recognized by the FDA as a validated endpoint for drug approval in neoadjuvant setting61. Third, the methods used to apply the PAM50 algorithm varied across trials. For example, 13 studies used the nCounter platform14,17,20,2229,31, 2 studies used RNA-seq data15,18 and 2 studies used microarray-based data16,21. Finally, we were only able to perform a study-level meta-analysis instead of a patient-level meta-analysis, which would have increased precision and homogeneity and enabled thorough exploration of potential effect moderators.

To conclude, our results demonstrate that the HER2-E subtype is a consistent biomarker of response following neoadjuvant anti-HER2-based regimens, with and without CT and beyond HR status. This biomarker, along with TILs and other biomarkers, such as PIK3CA mutations3942, either alone or in combination43, should be routinely incorporated in future prospective clinical trials designed to implement strategies to escalate and/or de-escalate systemic therapies11,1431.

Supplementary Material

1

Highlights.

  • We correlated the breast cancer intrinsic subtypes with pCR in HER2+ disease

  • The HER2-E signature was significantly and consistently associated with pCR after anti-HER2-based therapy

  • The HER2-E subtype was associated with pCR irrespective of hormone receptor status

  • The HER2-E subtype was associated with pCR also with chemo-free neoadjuvant schemes

Acknowledgements

With are grateful to Dario Bruzzese (associate professor of Statistics at the University of Naples Federico II) for his methodological suggestions.

Funding

Instituto de Salud Carlos III - PI16/00904 (to AP), Pas a Pas (to AP), Save the Mama (to AP), Breast Cancer Now - 2018NOVPCC1294 (to AP). Fundación Cientifica Asociación Española Contra el Cancer - Ayuda Postdoctoral AECC 2017 (to FB-M). Fundación SEOM, Becas FSEOM para Formación en Investigatión en Centros de Referencia en el Extranjero 2016 (to AF-M). NCI Breast SPORE program P50-CA58223 (to CMP) and Susan G. Komen (SAC-160074 (to CMP), and NCI 1R01CA229409 (to LAC). The Department of Defense grants W81XWH-17-1-0579 (to MFR) and W81XWH-17-1-0580 (to RS); NIH: SPORE Grant P50 CA186784 (to RS, CKO, and MFR); Cancer Center Grants (P30 CA125123); research grant from the Breast Cancer Research Foundation BCRF-18-145 (to RS and CKO).

Conflict of interest: FS has declared travel and accommodation expenses paid by Roche, Pfizer and Celgene. SDP has declared honoraria from Roche, Pfizer, Astra-Zeneca, Novartis, Celgene, Eli Lilly, Amgen and Eisai. AP has declared an immediate family member being employed by Novartis, personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo, travel, accommodations and expenses paid by Daiichi Sankyo, research funding from Roche and Novartis, consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb and patent PCT/EP2016/080056: HER2 AS A PREDICTOR OF RESPONSE TO DUAL HER2 BLOCKADE IN THE ABSENCE OF CYTOTOXIC THERAPY. OTHER AUTHORS CoI. PFC had declared consultant role for Novartis, Eli Lilly, Astra Zeneca and Tesaro, honoraria from BMS, Roche, Eli Lilly, Novartis and AstraZeneca, research funding from Novartis, Roche, BMS, Merck-KGa, Italian Ministry of Health, Veneto Secretary of Health and University of Padova. CMP is an equity stock holder and consultant of BioClassifier LLC and is also listed an inventor on patent applications on the Breast PAM50. LAC has declared that Companies who have provided funds to her institution in the past 1-2 years either for her service on advisory/consultative programs or sponsored research were Genentech, Roche, Novartis, Seattle Genetics, G1 Therapeutics, Immunomedics and Innocrin. SP has received honoraria for talks and travel grants from Roche outside of the submitted work and serves as an advisor/consultant to Polyphor. RS has declared research funding from AstraZeneca, GlaxoSmithKline, Gilead Sciences, and PUMA Biotechnology, and consulting/advisory role with compensation for Macrogenics, and Eli Lilly. CKO has declared research funding from AstraZeneca and GlaxoSmithKline, advisory boards for Tolmar Pharmaceuticals, Genentech, and AstraZeneca, DMC for Eli Lilly and stockholder of GeneTex. MFR has declared research funding from GlaxoSmithKline and Genentech. JCB is an employee of Novartis. The other authors have nothing to declare.

Footnotes

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Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

  • 1.Cronin KA, Harlan LC, Dodd KW, Abrams JS, Ballard-Barbash R. Population-based estimate of the prevalence of HER-2 positive breast cancer tumors for early stage patients in the US. Cancer Invest. 2010;28(9):963–968. doi: 10.3109/07357907.2010.496759 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol Off J Am Soc Clin Oncol. 2018;36(20):2105–2122. doi: 10.1200/JCO.2018.77.8738 [DOI] [PubMed] [Google Scholar]
  • 3.Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–792. doi: 10.1056/NEJM200103153441101 [DOI] [PubMed] [Google Scholar]
  • 4.Swain SM, Kim S-B, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14(6):461–471. doi: 10.1016/S1470-2045(13)70130-X [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688–1700. doi: 10.1016/S1470-2045(17)30717-9 [DOI] [PubMed] [Google Scholar]
  • 6.Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733–2743. doi: 10.1056/NEJMoa064320 [DOI] [PubMed] [Google Scholar]
  • 7.Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–1791. doi: 10.1056/NEJMoa1209124 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Mounsey LA, Deal AM, Keith KC, et al. Changing Natural History of HER2-Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies. Clin Breast Cancer. 2018;18(1):29–37. doi: 10.1016/j.clbc.2017.07.017 [DOI] [PubMed] [Google Scholar]
  • 9.Prat A, Pineda E, Adamo B, et al. Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast Edinb Scotl. 2015;24 Suppl 2:S26–35. doi: 10.1016/j.breast.2015.07.008 [DOI] [PubMed] [Google Scholar]
  • 10.Prat A, Carey LA, Adamo B, et al. Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer. J Natl Cancer Inst. 2014;106(8). doi: 10.1093/jnci/dju152 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 30 2019. doi: 10.1093/jnci/djz042 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Comprehensive molecular portraits of human breast tumors. Nature. 2012;490(7418):61–70. doi: 10.1038/nature11412 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol. 2011;5(1):5–23. doi: 10.1016/j.molonc.2010.11.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Llombart-Cussac A, Cortés J, Paré L, et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol. 2017;18(4):545–554. doi: 10.1016/S1470-2045(17)30021-9 [DOI] [PubMed] [Google Scholar]
  • 15.Carey LA, Berry DA, Cirrincione CT, et al. Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(6):542–549. doi: 10.1200/JCO.2015.62.1268 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Prat A, Bianchini G, Thomas M, et al. Research-based PAM50 subtype predictor identifies higher responses and improved survival outcomes in HER2-positive breast cancer in the NOAH study. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(2):511–521. doi: 10.1158/1078-0432.CCR-13-0239 [DOI] [PubMed] [Google Scholar]
  • 17.Swain SM, Tang G, Lucas PC, et al. Intrinsic subtypes of HER2-positive breast cancer and their associations with pathologic complete response (pCR) and outcomes: Findings from NSABP B-41, a randomized neoadjuvant trial. J Clin Oncol. 2018;36(15_suppl):580–580. doi: 10.1200/JCO.2018.36.15_suppl.580 [DOI] [Google Scholar]
  • 18.Fumagalli D, Venet D, Ignatiadis M, et al. RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial. JAMA Oncol. 2017;3(2):227–234. doi: 10.1001/jamaoncol.2016.3824 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Bianchini G, Parker JS, Carey LA, et al. Research-based PAM50 predicts risk of relapse in residual disease after anti-HER2 therapies. Ann Oncol. 2018;29(8_suppl):viii58–viii86. [Google Scholar]
  • 20.Bianchini G, Pusztai L, Pienkowski T, et al. Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial. Ann Oncol Off J Eur Soc Med Oncol. 2015;26(12):2429–2436. doi: 10.1093/annonc/mdv395 [DOI] [PubMed] [Google Scholar]
  • 21.Dieci MV, Prat A, Tagliafico E, et al. Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial. Ann Oncol. 2016;27(10):1867–1873. doi: 10.1093/annonc/mdw262 [DOI] [PubMed] [Google Scholar]
  • 22.Ignatiadis M, Van den Eynden G, Roberto S, et al. Tumor-Infiltrating Lymphocytes in Patients Receiving Trastuzumab/Pertuzumab-Based Chemotherapy: A TRYPHAENA Substudy. J Natl Cancer Inst. 2019;111(1):69–77. doi: 10.1093/jnci/djy076 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Holmes FA, Espina V, Liotta LA, et al. Pathologic complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling. BMC Res Notes. 2013;6:507. doi: 10.1186/1756-0500-6-507 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Swain SM, Ewer MS, Viale G, et al. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol Off J Eur Soc Med Oncol. 2018;29(3):646–653. doi: 10.1093/annonc/mdx773 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Gavilá J, Oliveira M, Pascual T, et al. Safety, activity, and molecular heterogeneity following neoadjuvant non-pegylated liposomal doxorubicin, paclitaxel, trastuzumab, and pertuzumab in HER2-positive breast cancer (Opti-HER HEART): an open-label, single-group, multicenter, phase 2 trial. BMC Med. 2019;17(1):8. doi: 10.1186/s12916-018-1233-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Pernas S, Petit A, Climent F, et al. Abstract P2-09-11: PAM50 intrinsic subtyping as a predictor of pathological complete response to neoadjuvant trastuzumab-based chemotherapy in early HER2-positive breast cancer. Cancer Res. 2018;78(4 Supplement):P2-09-11. doi: 10.1158/1538-7445.SABCS17-P2-09-11 [DOI] [Google Scholar]
  • 27.Prat A, Slamon D, Hurvitz S, et al. Abstract PD3-06: Association of intrinsic subtypes with pathological complete response (pCR) in the KRISTINE neoadjuvant phase 3 clinical trial in HER2-positive early breast cancer (EBC). Cancer Res. 2018;78(4 Supplement):PD3–06. doi: 10.1158/1538-7445.SABCS17-PD3-06 [DOI] [Google Scholar]
  • 28.Guarneri V, Dieci MV, Bisagni G, et al. De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2 weeks letrozole: results of the PerELISA neoadjuvant study. Ann Oncol. 2019;30(6):921–926. doi: 10.1093/annonc/mdz055 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Rimawi MF, Mayer IA, Forero A, et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(14):1726–1731. doi: 10.1200/JCO.2012.44.8027 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Prat A, De Angelis C, Pascual T, et al. Abstract P2-09-12: Independent validation of the HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer. Cancer Res. 2018;78(4 Supplement):P2-09-12. doi: 10.1158/1538-7445.SABCS17-P2-09-12 [DOI] [Google Scholar]
  • 31.Prat A, De Angelis C, Pascual T, et al. HER2-enriched subtype and ERBB2 mRNA as predictors of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer: A combined analysis of TBCRC006/023 and PAMELA trials. J Clin Oncol. 2018;36(15_suppl):509–509. doi: 10.1200/JCO.2018.36.15_suppl.509 [DOI] [Google Scholar]
  • 32.Cejalvo JM, Pascual T, Fernández-Martínez A, et al. Clinical implications of the non-luminal intrinsic subtypes in hormone receptor-positive breast cancer. Cancer Treat Rev. 2018;67:63–70. doi: 10.1016/j.ctrv.2018.04.015 [DOI] [PubMed] [Google Scholar]
  • 33.Curigliano G, Burstein HJ, Winer EP, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol Off J Eur Soc Med Oncol. 2017;28(8):1700–1712. doi: 10.1093/annonc/mdx308 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Salgado R, Denkert C, Campbell C, et al. Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial. JAMA Oncol. 2015;1(4):448–454. doi: 10.1001/jamaoncol.2015.0830 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(9):983–991. doi: 10.1200/JCO.2014.58.1967 [DOI] [PubMed] [Google Scholar]
  • 36.Conte PF, Griguolo G, Dieci MV, et al. PAM50 HER2-enriched subtype as an independent prognostic factor in early-stage HER2+ breast cancer following adjuvant chemotherapy plus trastuzumab in the ShortHER trial. J Clin Oncol. 2019;37(suppl):abstr 544. [Google Scholar]
  • 37.Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol Off J Eur Soc Med Oncol. 2014;25(8):1544–1550. doi: 10.1093/annonc/mdu112 [DOI] [PubMed] [Google Scholar]
  • 38.Griguolo G, Pascual T, Dieci MV, Guarneri V, Prat A. Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer. J Immunother Cancer. 2019;7. doi: 10.1186/s40425-019-0548-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Loibl S, Majewski I, Guarneri V, et al. PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. Ann Oncol Off J Eur Soc Med Oncol. 2016;27(8):1519–1525. doi: 10.1093/annonc/mdw197 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Baselga J, Cortés J, Im S-A, et al. Biomarker analyses in CLEOPATRA: a phase III, placebocontrolled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(33):3753–3761. doi: 10.1200/JCO.2013.54.5384 [DOI] [PubMed] [Google Scholar]
  • 41.Kim S-B, Wildiers H, Krop IE, et al. Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) vs. treatment of physician’s choice in previously treated HER2-positive advanced breast cancer. Int J Cancer. 2016;139(10):2336–2342. doi: 10.1002/ijc.30276 [DOI] [PubMed] [Google Scholar]
  • 42.Rimawi MF, De Angelis C, Contreras A, et al. Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Res Treat. 2018;167(3):731–740. doi: 10.1007/s10549-017-4533-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Veeraraghavan J, De Angelis C, Mao R, et al. A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer. Ann Oncol Off J Eur Soc Med Oncol. March 2019. doi: 10.1093/annonc/mdz076 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [Updated March 2011]. The Cochrane Collaboration; http://handbook.cochrane.org. [Google Scholar]
  • 45.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188. [DOI] [PubMed] [Google Scholar]
  • 46.Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–1558. doi: 10.1002/sim.1186 [DOI] [PubMed] [Google Scholar]
  • 47.Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol. 2001;54(10):1046–1055. [DOI] [PubMed] [Google Scholar]
  • 48.Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–634. doi: 10.1136/bmj.315.7109.629 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2017. https://www.R-project.org/. [Google Scholar]
  • 50.The Cochrane Collaboration. Review Manager (RevMan). Copenhagen: The Nordic Cochrane Centre; 2014. [Google Scholar]
  • 51.PROSPERO International prospective register of systematic reviews. https://www.crd.york.ac.uk/prospero/.
  • 52.Pernas S, Petit A, Climent F, et al. PAM50 Subtypes in Baseline and Residual Tumors Following Neoadjuvant Trastuzumab-Based Chemotherapy in HER2-Positive Breast Cancer: A Consecutive-Series From a Single Institution. Front Oncol. 2019;9. doi: 10.3389/fonc.2019.00707 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25–32. doi: 10.1016/S1470-2045(11)70336-9 [DOI] [PubMed] [Google Scholar]
  • 54.Peto R. Why do we need systematic overviews of randomized trials? Stat Med. 1987;6(3):233–244. [DOI] [PubMed] [Google Scholar]
  • 55.Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–182. doi: 10.1126/science.3798106 [DOI] [PubMed] [Google Scholar]
  • 56.Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet Lond Engl. 2014;384(9938):164–172. doi: 10.1016/S0140-6736(13)62422-8 [DOI] [PubMed] [Google Scholar]
  • 57.Von Minckwitz G, Untch M, Blohmer J-U, et al. Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes. J Clin Oncol 2012;30 (15):1796–804 [DOI] [PubMed] [Google Scholar]
  • 58.Nekljudova V, Loibl S , von Minckwitz G, et al. Trial-level Prediction of Long-Term Outcome Based on Pathologic Complete Response (pCR) After Neoadjuvant Chemotherapy for Early-Stage Breast Cancer (EBC). Contemp Clin Trials 2018; 71:194–198 [DOI] [PubMed] [Google Scholar]
  • 59.Broglio KR, Quintana M, Foster M, et al. Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis. JAMA Oncol 2016; 2(6):751–76 [DOI] [PubMed] [Google Scholar]
  • 60.Spring LM, Fell G, Arfe A, et al. Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and mortality, stratified by breast cancer subtypes and adjuvant chemotherapy usage: Individual patient-level meta-analyses of over 27,000 patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS2-03 [Google Scholar]
  • 61.FDA Guidance for Industry. Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. Available at: https://www.fda.gov/media/83507/download. Last accessed: 02/12/2020
  • 62.Rimawi MF, Niravath P, Wang T, et al. TBCRC023: A Randomized Phase II Neoadjuvant Trial of Lapatinib Plus Trastuzumab Without Chemotherapy for 12 vs. 24 Weeks in Patients with HER2-positive Breast Cancer. Clin Cancer Res. 2019; doi: 10.1158/1078-0432.CCR-19-0851 [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
  • 63.Dieci MV, Vernaci G, Guarneri V. Escalation and de-escalation in HER2 positive early breast cancer. Curr Opin Oncol. 2019;31(1):35–42. doi: 10.1097/CCO.0000000000000492 [DOI] [PubMed] [Google Scholar]
  • 64.Veeraraghavan J, De Angelis C, Reis-Filho JS, et al. De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance. Breast Edinb Scotl. 2017;34 Suppl 1:S19–S26. doi: 10.1016/j.breast.2017.06.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Pondé N, Gelber RD, Piccart M. PERSEPHONE. NPJ Breast Cancer. 2019;5:1. doi: 10.1038/s41523-018-0098-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Tolaney SM, Guo H, Pernas S, et al. Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2019;37(22):1868–1875. doi: 10.1200/JCO.19.00066 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Metzger Filho O, Viale G, Trippa L, et al. HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: Results from a prospective clinical trial. J Clin Oncol. 2019;37(15_suppl):502–502. doi: 10.1200/JCO.2019.37.15_suppl.502 [DOI] [Google Scholar]
  • 68.Berruti A, Amoroso V, Gallo F, et al. Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. J Clin Oncol. 2014;32(34):3883–3891. doi: 10.1200/JCO.2014.55.2836. [DOI] [PubMed] [Google Scholar]
  • 69.Korn EL, Sachs MC, McShane LM. Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer. Ann Oncol. 2016;27(1):10–15. doi: 10.1093/annonc/mdv507 [DOI] [PMC free article] [PubMed] [Google Scholar]

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